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Abstract：
Ibudilast (MN-166) is an inhibitor of macrophage migration inhibitory factor (MIF) and phosphodiesterases 3,4,10 and 11 (Gibson et al., 2006; Cho et al., 2010). Ibudilast attenuates CNS microglial activation and secretion of pro-inflammatory cytokines (Fujimoto et al., 1999; Cho et al., 2010). In vitro evidence suggests that ibudilast is neuroprotective by suppressing neuronal cell death induced by microglial activation. People with ALS have increased microglial activation measured by [11C]PBR28-PET in the motor cortices. The primary objective is to determine the impact of ibudilast on reducing glial activation and neuroaxonal loss in ALS, measured by PBR28-PET and serum Neurofilament light (NfL). The secondary objectives included determining safety and tolerability of ibudilast high dosage (up to 100 mg/day) over 36 weeks. In this open label trial, 35 eligible ALS participants underwent ibudilast treatment up to 100 mg/day for 36 weeks. Of these, 30 participants were enrolled in the main study cohort and were included in biomarker, safety and tolerability analyses. Five additional participants were enrolled in the expanded access arm, who did not meet imaging eligibility criteria and were included in the safety and tolerability analyses. The primary endpoints were median change from baseline in (a) PBR28-PET uptake in primary motor cortices, measured by standard uptake value ratio (SUVR) over 12-24 weeks and (b) serum NfL over 36-40 weeks. The secondary safety and tolerability endpoints were collected through Week 40. The baseline median (range) of PBR28-PET SUVR was 1.033 (0.847, 1.170) and NfL was 60.3 (33.1, 219.3) pg/ml. Participants who completed both pre and post-treatment scans had PBR28-PET SUVR median(range) change from baseline of 0.002 (-0.184, 0.156) , P = 0.5 (n = 22). The median(range) NfL change from baseline was 0.4 pg/ml (-1.8, 17.5), P = 0.2 (n = 10 participants). 30(86%) participants experienced at least one, possibly study drug related adverse event. 13(37%) participants could not tolerate 100 mg/day and underwent dose reduction to 60-80 mg/day and 11(31%) participants discontinued study drug early due to drug related adverse events. The study concludes that following treatment with ibudilast up to 100 mg/day in ALS participants, there were no significant reductions in (a) motor cortical glial activation measured by PBR28-PET SUVR over 12-24 weeks or (b) CNS neuroaxonal loss, measured by serum NfL over 36-40 weeks. Dose reductions and discontinuations due to treatment emergent adverse events were common at this dosage in ALS participants. Future pharmacokinetic and dose-finding studies of ibudilast would help better understand tolerability and target engagement in ALS.
摘要：
异丁司特（MN-166）是巨噬细胞迁移抑制因子（MIF）和磷酸二酯酶3,4,10和11的抑制剂（Gibson等人。,2006；Cho等人。,2010).异丁司特减弱CNS小胶质细胞活化和促炎细胞因子的分泌(Fujimoto等人。,1999；Cho等人。,2010).体外证据表明，异丁司特通过抑制小胶质细胞活化诱导的神经元细胞死亡而具有神经保护作用。患有ALS的人在运动皮层中通过[11C]PBR28-PET测量的小胶质细胞活化增加。主要目的是确定异丁司特对减少ALS神经胶质激活和神经轴突丢失的影响，通过PBR28-PET和血清神经丝光（NfL）测量。次要目标包括在36周内确定异丁司特高剂量（最高100mg/天）的安全性和耐受性。在这个开放标签试验中，35名符合条件的ALS参与者接受了依丁司特治疗，每天100mg，持续36周。其中,30名参与者被纳入主要研究队列，并被纳入生物标志物，安全性和耐受性分析。另外五名参与者加入了扩大的进入机构，不符合影像学检查合格标准的患者被纳入安全性和耐受性分析.主要终点是（a）初级运动皮层中的PBR28-PET摄取自基线的中位数变化，通过12-24周的标准摄取值比率（SUVR）和（b）36-40周的血清NfL来测量。通过第40周收集次要安全性和耐受性终点。PBR28-PETSUVR的基线中位数（范围）为1.033（0.847，1.170），NfL为60.3（33.1，219.3）pg/ml。完成治疗前后扫描的参与者的PBR28-PETSUVR从基线的中位数（范围）变化为0.002（-0.184，0.156），P=0.5(n=22)。NfL相对于基线的中位数（范围）变化为0.4pg/ml（-1.8，17.5），P=0.2（n=10）。30名（86%）参与者至少经历过一次，可能研究药物相关的不良事件。13名（37％）参与者不能耐受100mg/天，剂量减少至60-80mg/天，11名（31％）参与者由于药物相关的不良事件而提前停止研究药物。该研究得出的结论是，在ALS参与者中使用异丁司特治疗高达100mg/天之后，（a）通过PBR28-PETSUVR在12-24周内测量的运动皮质胶质细胞活化或（b）CNS神经轴突丢失没有显着降低，在36-40周内通过血清NfL测量。在ALS参与者中，由于治疗引起的不良事件而导致的剂量减少和中止是常见的。未来异丁司特的药代动力学和剂量发现研究将有助于更好地理解ALS的耐受性和目标参与。
